This is a renewal application for the Northwestern University Udall Center of Excellence in Parkinson's disease Research, now in its 10th year. In the last award period, this highly productive research team made fundamental insights into the mechanisms underlying Parkinson's disease, resulting in over 50 peer-reviewed publications. Our studies also motivated a successful Phase II clinical trial with isradipine. The program continues under the direction of Dr. D. James Surmeier. There are 4 scientific projects, 1 translational project, an administrative core and a molecular biology core built around 2 central themes: 1) the determinants of selective neuronal vulnerability in Parkinson's disease and 2) the determinants of the network pathophysiology responsible for the core motor symptoms of the disease. Project 1, directed by Dr. Surmeier, builds upon ground-breaking work in the last grant period to pursue the role of the pedunculopontine nucleus and nicotine in regulating oxidant stress in substantia nigra dopaminergic neurons. Project 2, directed by Dr. Savio Chan, pursues the mechanisms governing the emergence of synchronous rhythmic bursting in globus pallidus neurons in Parkinson's disease, focusing on a novel class of these neurons that project to the striatum. Project 3, directed by Dr. Mark Bevan, explores the role of cortical and pallidal input t the subthalamic nucleus in driving oscillatory behavior in Parkinson's disease. Project 4, directed by Dr. Charles Wilson, explores the mechanisms underlying the symptomatic benefit of deep brain stimulation. Project 5, directed by Dr. Richard Miller, is a translational project; this project will test the neuroprotective potential of a novel selective antagonist of Cav1.3 L-type Ca2+ channels, as well as two anti-inflammatory agents; this project will also test the ability of novel gene therapy targeting GluN2D-containing glutamate receptors to produce symptomatic relief in a Parkinson's disease model. These projects make use of advanced molecular, optogenetic, pharmacogenomics, imaging and electrophysiological approaches to achieve their aims. The administrative core will oversee the program budget/subcontract arrangements, biannual meetings, external and internal advisory committees, archiving and distribution of program publications, compilation and submission of annual NIH program renewal applications, and maintenance of a program web page. The molecular core will provide gene expression analysis for each of the projects, provide consultation and assistance for genotyping, and provide assistance in the design and construction of viral vectors for gene knockdown and to provide assistance in the design and construction of viral vectors for gene delivery. The successful attainment of our programmatic goals should bring us closer to meeting the two grand challenges facing the Parkinson's disease research community: to develop a disease-modifying therapy and to develop better, longer lasting symptomatic therapies.